Process of resolving phenylpropionic acids using α-methylbenzylamine

ABSTRACT

A process for the production of a product which is enriched in a desired enantiomer of a phenylpropionic acid selected from ibuprofen and flurbiprofen, or their pharmaceutically acceptable salts, which comprises a resolution stage, a recrystallization stage, an optional liberation stage, and an optional salt preparation stage. A substantially racemic mixture of the phenylpropionic acid is contacted with an enantiomer of α-methylbenzylamine, in specific ratios, to produce the enantiomerically enriched product.

This application is a 371 of PCT/EP93/03376 filed Nov. 30, 1993.

FIELD OF THE INVENTION

The present invention relates to the production of substantially pureenantiomers of phenylpropionic acids selected from ibuprofen,flurbiprofen and pharmaceutically acceptable salts thereof, inparticular their α-methylbenzylamine, lysine and sodium salts.

DESCRIPTION OF THE RELATED ART

Ibuprofen, the chemical name of which is 2-(4-isobutylphenyl)propionicacid and flurbiprofen, the chemical name of which is2-(2-fluoro-4-biphenylyl)propionic acid are well known medicaments withanti-inflammatory, antipyretic and analgesic activities. Known uses ofibuprofen and flurbiprofen include the treatment of pain andinflammation in musculoskeletal disorders such as rheumatic disease, andthe treatment of pain in a variety of other disorders, for exampleheadache, neuralgia and dysmenorrhoea.

Both ibuprofen and flurbiprofen contain a single chiral centre at anasymmetrically substituted carbon atom and therefore both exist in twoenantiomeric forms. It is known that S(+)-ibuprofen is the active agentand that R(-)-ibuprofen may be incompletely converted intoS(+)-ibuprofen in humans. It is also known that S(+)-flurbiprofen is theactive agent. R(-)-flurbiprofen is not converted into the (S)-enantiomerin humans, although it has been suggested that R(-)-flurbiprofen hasanalgesic activity only (international patent application WO 92/04018[Paz]). Ibuprofen and flurbiprofen have been marketed previously as theracemic mixture. However in certain circumstances it may be advantageousto administer substantially one enantiomer only. Therefore it isdesirable to provide improved processes for production of a productenriched in a desired enantiomer of a phenylpropionic acid selected fromibuprofen and flurbiprofen.

European Patent Application 0362476 (Paz) describes the separation ofenantiomeric forms of aryl propionic acids by selective crystallisationof a diastereomeric salt in a polar solvent. Use of polar solvents arestated to be more favourable than apolar solvents, which teaches awayfrom using the specific solvent mixture in the process of the presentinvention.

U.S. Pat. No. 5,015,764 (Manimaran) relates to the preparation ofaliphatic carboxylic acids including ibuprofen and flurbiprofen bytreating a solution of their salts with a chiral organic base toselectively precipitate the less soluble diastereoisomer. There is nodisclosure of the use of the specific solvent mixture used in theprocess of the present invention.

European Patent Application 0437369 describes the preparation of(S)-ibuprofen-(S)-lysine salts by contacting racemic ibuprofen with anequimolar amount of (S)-lysine in an aqueous organic solvent mixture,separating any suspended solid from the mixture, cooling the clearmixture until it is supersaturated with respect to both the(R)-ibuprofen-(S)-lysine and the (S)-ibuprofen-(S)-lysine salts,contacting the supersaturated solution with a slurry of(S)-ibuprofen-(S)-lysine salt and separating the formed crystallineS)-ibuprofen-(S)-lysine salt.

International Patent Application WO 92/20334 Boots) describes thepreparation of the sodium salt of (S)-ibuprofen.

SUMMARY OF THE INVENTION

The present invention provides a process for the production of a productwhich is enriched in a desired enantiomer of a phenylpropionic acidselected from ibuprofen and flurbiprofen which comprises the followingstages:

(a) a resolution stage, in which an α-methylbenzylamine salt of thephenylpropionic acid is prepared which is enriched in the desiredenantiomer by contacting, in a mixture of toluene and methanol assolvent, a substantially racemic mixture of the phenylpropionic acidwith an enantiomer of α-methylbenzylamine, the respective molar ratio ofthe substantially racemic phenylpropionic acid to theα-methylbenzylamine being in the range of about 1:0.25 to about 1:1;

b) a recrystallization stage, in which the resulting enriched salt isrecrystallised from a mixture of methanol and toluene to give anα-methylbenzylamine salt of the phenylpropionic acid which is furtherenriched in the desired enantiomer;

c) an optional liberation stage, in which the phenylpropionic acid whichis further enriched in the desired enantiomer is liberated from therecrystallised salt.

d) an optional salt-preparation stage in which a solid salt of thephenylpropionic acid further enriched in the desired enantiomer isisolated, the solid salt optionally being even further enantiomericallyenriched in the desired enantiomer.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a diagrammatic flowchart of the process of the presentinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In preferred embodiments of the process of the present invention, thedesired enantiomer of the phenylpropionic acid is the (S)-enantiomerand:

a) in the resolution stage, the substantially racemic phenylpropionicacid and (S)-α-methylbenzylamine are used in a respective molar ratio ofabout 1:0.35 to about 1:0.8, for example about 1:0.4 to about 1:0.6 andthe preparation takes place in a mixture of methanol and toluene, inwhich the toluene comprises at least about 50%, more preferably fromabout 60% to about 90%, most preferably from about 70% to about 80%, ofthe total mixture by volume; the temperature of the mixture is in therange from about 30° C. to about 70° C., preferably from about 40° C. toabout 60° C., to form a supersaturated solution; from which aphenylpropionic acid -(S)-α-methylbenzylamine salt enriched in the(S)-enantiomer of the phenylpropionic acid is crystallised, for examplewhen the solution is cooled to a temperature in the range from about-10° C. to about 30° C., preferably from about 0° C. to about 5° C.;

(b) in the recrystallisation stage the preferred solvent is a mixture ofmethanol and toluene in which the toluene comprises at least about 25%,more preferably from about 50% to about 80%, most preferably from about60% to about 70%, of the total mixture by volume; from which aphenylpropionic acid -(S)-α-methylbenzylamine salt further enriched inthe (S)-enantiomer of the phenylpropionic acid is crystallised, forexample when the solution is cooled to a temperature in the range fromabout -10° C. to about 30° C., preferably from about 0° C. to about 5°C.;

(c) in the liberation stage the (S)-α-methylbenzylamine salt offurther-(S)-enriched-phenylpropionic acid, obtained from therecrystallisation stage, is acidified (for example with hydrochloricacid) in a water-immiscible solvent to produce a solution of liberated(S)-enriched-phenylpropionic acid in the water-immiscible solvent and anaqueous solution of a salt of (S)-α-methylbenzylamine (for example, thehydrochloride salt) from which (S)-α-methylbenzylamine can be liberatedso that it can be reused in a subsequent resolution stage (a), forexample by basifying the solution and extracting the liberated base intotoluene;

(d) optionally in the salt-preparation stage the solution offurther-(S)-enriched-phenylpropionic acid in the water-immisciblesolvent obtained from the liberation stage (c) may be further processedby one or more of the following methods:

(i) crystallisation and isolation of the solid(S)-enriched-phenylpropionic acid from the solution;

(ii) removal of the solvent by distillation to give a melt which can beused in step (v) below;

(iii) where the phenylpropionic acid is ibuprofen, contact with anaqueous solution of a sodium-containing base (e.g. sodium hydroxide) toproduce an aqueous solution of the sodium salt of ibuprofen, which isseparated from the water-immiscible solvent, the aqueous solution thenbeing diluted with acetone to crystallisefurther-(S)-enriched-sodium-ibuprofen; and

(iv) where the phenylpropionic acid is ibuprofen, contact with(S)-lysine and water in which the respective molar ratio of ibuprofen to(S)-lysine is in the range 1:0.5 to 1:1 to give an aqueous solution ofthe (S)-lysine salt which is separated from the immiscible solvent,ethanol then being added to the aqueous solution to crystallisefurther-(S)-enriched-ibuprofen-(S)-lysine. The product of steps d(i) tod(iii) above may be used in one or more of the following further steps:

(v) the solid from step d(i) above or the melt from step d(ii) which isseparated and reacted in an aqueous ethanolic solution with (S)-lysinein which the molar ratio of the phenylpropionic acid to (S)-lysine is inthe range 1:0.5 to 1:1, to give, after crystallisation and separation,an (S)-lysine salt of the further-(S)-enriched-phenylpropionic acid;

(vi) acidification of the further-(S)-enriched-sodium ibuprofen fromstep d(iii) above in the presence of a water immiscible solvent, such asheptane, to produce a solution of further-(S)-enriched ibuprofen in thewater-immiscible solvent which is separated. Solid(S)-enriched-ibuprofen is then crystallised and isolated; and

(vii) acidification of the aqueous solution of thefurther-S-enriched-sodium-ibuprofen from d(iii) above at elevatedtemperature (for example at 60° C.) to give a melt which is separatedfrom the aqueous layer and treated as described in (v) above.

In more preferred embodiments of the process of the present inventionthe phenylpropionic acid is ibuprofen and the desired enantiomer is the(S)-enantiomer. In this more preferred embodiment:

(a) the resolution stage produces a (S)-α-methylbenzylamine salt of(S)-enriched ibuprofen of an enantiomeric purity from about 80% to about95% by weight, and a first mother liquor comprising(R)-enriched-ibuprofen, which is used in a racemisation stage (e) toproduce substantially racemic ibuprofen which is introduced as part ofthe starting material used in a subsequent resolution stage (a);

(b) the recrystallisation stage comprises two steps:

(i) a first recrystallisation step comprising recrystallising the(S)-enriched-ibuprofen-(S)-α-methylbenzylamine produced from theresolution stage (a) , to produce(S)-enriched-ibuprofen-(S)-methylbenzylamine preferably of anenantiomeric purity from about 90% to about 99.9%, more preferably fromabout 94% to about 99%, by weight, and a second mother liquor comprising(S)-enriched ibuprofen-(S)-α-methylbenzylamine of an enantiomeric purityfrom about 40% to about 70%, more preferably from about 40% to about 60%by weight, the second mother liquor being introduced as part of thesolvent used in a subsequent resolution step (a); and

(ii) a second recrystallisation step comprising recrystallisation of the(S)-enriched-ibuprofen-(S)-α-methylbenzylamine produced from the firstrecrystallisation step (b) (i) to produce substantially enantiomericallypure (S)-ibuprofen-(S)-α-methylbenzylamine, preferably of an enantiomerpurity of about 99%, and a third mother liquor comprising(S)-enriched-ibuprofen-(S)-α-methylbenzylamine of an enantiomeric purityfrom about 85% to about 95% by weight, preferably from about 88% toabout 95% by weight, the third mother liquor being introduced as part ofthe solvent used in into a subsequent first recrystallisation step (b)(i).

In a most preferred embodiment of the invention, the first mother liquorfrom the resolution stage (a) is subjected to azeotropic distillation toremove substantially all the methanol at temperatures which avoidsubstantially the formation of by-products, the distillate being reusedas part of the solvent in a subsequent resolution stage (a). The residueremaining after the distillation above may be acidified, with forexample hydrochloric acid, to give an aqueous solution of a(S)-α-methylbenzylamine salt, for example (S)-α-methylbenzylaminehydrochloride, and an organic phase comprising (R)-enriched ibuprofen.The aqueous solution is then separated and basified to give free(S)-α-methylbenzylamine which is extracted into toluene and reused asthe resolving agent at the start of a subsequent resolution stage (a)along with (S)-α-methylbenzylamine recovered in the liberation stage(s).The organic phase comprising (R)-enriched-ibuprofen may be racemised ina racemisation stage (e) by any known method to produce substantiallyracemic ibuprofen which may then be introduced as part of the solventused at the start of a subsequent resolution stage (a).

Preferably at each stage of the process of the present invention liquorsnot comprising the phenylpropionic acid enriched in the desiredenantiomer may be recycled by using them in previous stages of theprocess. Combining the resolution stage (a) and recrystallisation stage(b) with a racemisation stage (e) and a recovery stage for the(S)-α-methylbenzylamine resolving agent has the advantage of avoidingtreatment of multiple streams of liquors produced from each stage andreduces the production cost by saving time, energy and raw materials.

Optionally the recrystallisation stage in the process described abovemay include a third and/or subsequent recrystallisation step.

This preferred combined process is illustrated by reference to thedrawing in which FIG. 1 is a diagrammatic flow chart of a preferredprocess of the invention for production of (S)-ibuprofen in which theletters refer to the stages or steps labelled (a), (b)(i), (b)(ii), (c),(d) and (e) in the above described processes and; the numbers 1 to 3indicate the first to third mother liquors respectively, the number 4indicates the recycled (S)-α-methylbenzylamine and the number 5indicates the recycled racemised ibuprofen. In FIG. 1, dotted linesindicate recycled materials and solid lines indicates materialincreasing in enrichment of (S)-ibuprofen in the direction of the arrow.

Resolution stage (a) yields an(S)-enriched-ibuprofen-(S)-α-methylbenzylamine product which is used asthe starting material for the first recrystallisation step (b) (i). Thefirst mother liquors (1) from the resolution stage (a) pass to aracemisation stage (e) from which racemic ibuprofen (5) is recycled toform part of the starting material for a subsequent resolution stage (a)and recovered (S)-α-methylbenzylamine (4) is recycled to be used as partof the resolving agent for a subsequent resolution stage (a). The secondmother liquors (2) from the first recrystallisation step (b)(i) arerecycled for use in a subsequent resolution step (a). The product of thefirst recrystallisation step (b)(i) undergoes a second recrystallisationstep (b)(ii) to give (S)-ibuprofen-(S)-α-methylbenzylamine of increasedenantiomeric purity and a third mother liquor which is recycled to formpart of the solvent used in a subsequent first recrystallisation step(b)(i). The product from the second recrystallisation step (b)(ii) isthen used in a liberation stage (c) to give (S)-ibuprofen of highenantiomeric purity. (S)-α-Methylbenzylamine (4) which is also liberatedin the liberation stage (c) is recycled to be used as part of theresolving agent for a subsequent resolution stage (a). The liberated(S)-ibuprofen may then be used in an optional salt-preparation stage (d)to form salts (for example the sodium or (S)-lysine salt) containing(S)-ibuprofen of even higher enantiomeric purity.

A product of the above processes, when the phenylpropionic acid isibuprofen and the desired enantiomer is the (S)-enantiomer, may be usedto prepare a (S)-lysine salt of (S)-enriched ibuprofen by contacting theliberated (S)-enriched- ibuprofen with (S)-lysine, preferably with astoichiometric amount or less of (S)-lysine to produce a (S)-lysine saltof further-(S)-enriched-ibuprofen, more preferably the molar ratio ofibuprofen to (S)-lysine being in the range from about 1:0.5 to about 1:1preferably about 1:0.5 to about 1:0.95. The liberated(S)-enriched-ibuprofen can also be contacted with sodium hydroxide toproduce further-(S)-enriched sodium ibuprofen (see for exampleInternational Patent Application WO 92/20334).

In a further preferred embodiment the process of the present inventiongives (S)-ibuprofen, and salts thereof, of high enantiomeric purity.

Surprisingly it has also been found that (S)-enriched-flurbiprofen maybe crystallised from toluene with the efficient removal of the otherenantiomer to give (S)-flurbiprofen of a high enantiomeric purity.

It will be readily understood that if the production of R(-)-ibuprofen,R(-)-flurbiprofen or their pharmaceutically acceptable salts is desired,the above processes can be readily adapted for production of theR(-)-ibuprofen, R(-)-flurbiprofen or their pharmaceutically acceptablesalts by substituting (R)-α-methylbenzylamine for(S)-α-methylbenzylamine as the resolving agent in the resolution stage(a) of the processes of the present invention, with correspondingmodifications to the subsequent stages.

The invention will now be illustrated by the following Examples.

Example 1 Resolution of Ibuprofen by Preparation of(S)-Enriched-Ibuprofen-(S)-α-Methylbenzylamine [Resolution Stage (a)]

Recycled racemic ibuprofen (530 kg) was dissolved in toluene (1335 l)and methanol (900 l) was added and the mixture was heated with stirringto 66° C. Recycled (S)-α-methylbenzylamine (247 kg) in toluene (200 l)was added over 3 hours whilst the temperature was maintained in therange 65°-70° C. The mixture was cooled finally to 0° to 5° C. withstirring and stirred at this temperature for one hour. The desiredproduct was collected by filtration, washed with toluene (600 l). Theproduct contained (S)-α-methylbenzylamine salt of (S)-enriched-ibuprofenof an enantiomeric purity of 89.3% by weight. The mother liquors wereretained for processing in a similar manner to that described in Example6.

Example 2 Recrystallisation Stage of the (S)-α-Methylbenzylamine Salt of(S)-Enriched Ibuprofen [Recrystallisation Stage (b)] Example 2(a) [FirstRecrystallisation Step (b)(i)]

(S)-enriched-ibuprofen-(S)-α-methylbenzylamine (635 kg) of anenantiomeric purity of 85.5% by weight, obtained in a similar manner tothat described in Example 1 above), toluene (598 l) and recycled secondmother liquor (2350 l, obtained from Example B2 below, comprising(S)-enriched-ibuprofen-(S)-α-methylbenzylamine (214 kg) and methanol(800 l) stirred, heated and dissolved at 67° C. and then cooled finallya temperature in the range of 0° C. to 5° C. The resulting solid wascollected by filtration. The product was(S)-enriched-ibuprofen-(S)-α-methylbenzylamine of an enantiomeric purityof 94.1% by weight.

Example 2(b) [Second Recrystallisation Step (b)(ii)]

In a similar manner to the first recrystallisation step described inExample 2(a) above, the (S)-enriched-ibuprofen-(S)-α-methylbenzylamineof an enantiomeric purity of 91.4% by weight (629 kg, obtained in asimilar manner to that described in Example 2(a) above) wasrecrystallised from a mixture of toluene (115 l), and washed withtoluene (200 l) so that it had an enantiomeric purity of 98.5% byweight.

Examples 2(a) and 2(b) illustrate that a substantial upgrading in theenantiomeric purity of (S)-enriched-ibuprofen-(S)-α-methylbenzylaminecan be achieved at the recrystallisation stage in the process of thepresent invention.

Example 3(a) Liberation of (S)-Enriched Ibuprofen in Toluene Solution[Liberation Stage (c)]

The (S)-enriched-ibuprofen-(S) -α-methylbenzylamine salt (485 kg,prepared as described in Example 2(b) above), toluene (814 l), water(300 l) and concentrated hydrochloric acid of specific gravity 1.18 (170kg) was stirred for 30 minutes. The lower aqueous layer comprising(S)-α-methylbenzylamine hydrochloride was separated, combined with theaqueous liquors as described in Example 6 below before being recycled asdescribed in Example 1 above. The upper layer comprising a toluenesolution of (S)-enriched-ibuprofen was washed with water (100 l) to give920 kg of a solution containing 300 kg of (S)-enriched-ibuprofen ofenantiomeric purity of 98.5% by weight.

Example 3(b) Purification of (S)-Enriched Ibuprofen

A solution of (S)-enriched ibuprofen having an enantiomeric purity of98.2% (180 kg) in toluene (1221 kg) was washed with water. Water (220 l)and aqueous sodium hydroxide solution (47 l--specific gravity 1.5) wereadded and the mixture heated to 60° C. and allowed to settle for fourhours. The lower aqueous layer was separated and the toluene layerwashed with water. The aqueous washing was combined with the aqueouslayer. Residual toluene was removed by distillation and heptane (250 l)and the concentrated hydrochloric acid (78 kg--specific gravity 1:18)were added. The heptane layer was separated, washed with water andcooled to -10° C. (S)-Enriched ibuprofen having an enantiomeric purityof greater than 99% was collected by filtration and dried in vacuo.(Yield 166 kg).

Example 4(a) Preparation of (S-Enriched Ibuprofen-(S)-Lysine [SaltPreparation Stage (d)]

Examples 4.1 to 4.12 were performed as described below with reference toTable 1. Ibuprofen enriched in the (S)-enantiomer (100 g of a materialcontaining `a`% of the (S)-enantiomer) was dissolved in ethanol (900 ml)at ambient temperature. A solution of (S)-lysine monohydrate (`b` g) ina mixture of water (`c` ml) and ethanol (`d` ml) was prepared. Theibuprofen solution and the (S)-lysine solution were added simultaneouslyat equimolar rates over a period of one hour to a suspension of(S)-ibuprofen-(S)-lysine salt (9.5 g) in water (11 ml) and ethanol (125ml) which had been stirred at 20° C. for 10 minutes. The mixture wasthen cooled to 0° C. over one hour and then cooled to -10° C. Themixture was stirred at -10° C. for two hours. The resulting solid wascollected by filtration, washed with ethyl acetate and dried in vacuo at35° C. to give (S)-enriched-ibuprofen-(S)-lysine salt of an enantiomericpurity of `e`% by weight.

                  TABLE 1                                                         ______________________________________                                        Example  a         b      c       d   e                                       ______________________________________                                        4.1      94.54     60.3   79      55  98.9                                    4.2      99.16     60.3   79      55  99.8                                    4.3      91.1      60.3   79      55  98.4                                    4.4      94.54     67.5   85.5    55  98.7                                    4.5      94.54     64     82      55  98.6                                    4.6      91.1      67.5   85.5    55  97.8                                    4.7      99.16     64     82      55  99.7                                    4.8      99.16     67.5   85.5    55  99.7                                    4.9      91.1      64     82      55  97.8                                    4.10     94.54     60.3   79      55  98.5                                    4.11     94.54     64     82      55  98.6                                    4.12     99.16     67.5   85.5    55  99.7                                    ______________________________________                                    

Examples 4.1 to 4.12 illustrate that a substantial upgrading in theenantiomeric purity of (S)-enriched-ibuprofen-(S)-lysine salt can beachieved at the preparation stage in the process of the presentinvention.

Example 4 Preparation of S-Enriched-Ibuprofen-(S)-Lysine (SaltPreparation Stage (d)

A solution of (S)-enriched ibuprofen (30 g) in toluene (20 g) was heatedat 60° to 70° C. with (S)-lysine (40 g of a 50% w/w aqueous solution)and water (20 ml). The lower aqueous layer was separated and residualsolvent removed by distillation. Ethanol (460 ml) was added and themixture heated to 50° to 55° C. and then cooled to 0° C. to -10° C. forthirty minutes. Crystalline (S)-enriched-ibuprofen-(S)-lysine wascollected, washed with ethyl acetate (50 ml) and dried in vacuo.

Example 5 Preparation of (S)-Enriched Ibuprofen Sodium Salt [SaltPreparation Stage (d)]

A solution of (S)-enriched ibuprofen having an enantiomeric purity of95.5% (211 kg) in toluene (797 kg) was heated to 60° C. with water (300l) and aqueous sodium hydroxide solution (52 l--specific gravity 1.5)and allowed to settle for four hours. The aqueous layer was separatedand the toluene layer washed with water. The aqueous washings and theaqueous layer were combined and residual toluene removed bydistillation. Acetone (1684 kg) was added and the mixture cooled to 20°C. The sodium salt of (S)-enriched ibuprofen dihydrate (having anenantiomeric purity of 99.9%) separated, was collected by filtration anddried in vacuo. (Yield 143.5 kg).

Example 6 Treatment of the First Mother Liquors From the ResolutionStage

A mixture of the first mother liquors from the resolution stage wasconcentrated by distillation to remove methanol and toluene for recoveryand subsequent reuse. Water (300 l) and concentrated hydrochloric acid(170 kg--specific gravity 1.18) were added and the mixture stirred. Theaqueous layer containing (S)-α-methylbenzylamine hydrochloride wasseparated and combined with the aqueous solution of(S)-α-methylbenzylamine hydrochloride from Example 3(a). The combinedsolutions were basified with aqueous sodium hydroxide solution (340l--specific gravity 1.5). Toluene (500 l) was added and the resultingsolution of (S)-α-methylbenzylamine used in a subsequent resolutionstage performed in a similar manner to that described in Example 1.

Methanol (300 l) and concentrated sulphuric acid was heated under refluxfor 2 hours. The upper organic layer was separated and heated underreflux with methanol (75 l) and concentrated sulphuric acid (15 l) fortwo hours. The upper layer was separated and heated with solid sodiumhydroxide (175 kg). Methanol was removed by distillation and the residueacidified with a mixture of concentrated hydrochloric acid (353 kg) andwater (1750 l). The upper toluene layer containing racemic ibuprofen waswashed with water and used in the resolution stage of a subsequentpreparation similar to that described in Example 1.

Example 7 Resolution of Flurbiprofen by Preparation of(S)-Enriched-Flurbiprofen-(S)-α-Methylbenzylamine

Racemic flurbiprofen (61.0 g) was dissolved in a mixture of methanol (40ml) and toluene (160 ml). The mixture was heated to 60° C. and(S)-α-methylbenzylamine 16.9 ml was added over 10 minutes. A seedcrystal of (S)-flurbiprofen-(S)-α-methylbenzylamine was added to thereaction mixture which was then cooled to 0° to 5° C., and held at thattemperature for one hour. The precipitate was collected by filtration togive a (S)-α-methylbenzylamine salt of (S)-enrichedflurbiprofen-(S)-α-methylbenzylamine of an enantiomeric purity of 92.2%.After recrystallisation of the precipitate from a mixture of methanol(48 ml) and toluene (192 ml), afurther-(S)-enriched-flurbiprofen-(S)-α-methylbenzylamine of anenantiomeric purity of 98.5% was obtained.

The mother liquor obtained from the recrystallisation was acidified withc. HCl (10 ml) and water (25 ml) and stirred at 25° C. for 15 minutes.The lower aqueous layer containing the (S)-α-methylbenzylamine wascollected and reused. The upper organic layer contained a mixture of theflurbiprofen acid enantiomers in the weight ratio 41:5%:58.5%, S(+) toR(-) respectively. This flurbiprofen was transformed into itsmethylester which was racemised, converted back to racemic flurbiprofenwith sodium hydroxide and reintroduced into the resolution step above.

Example 8 Preparation of (R)-Flurbiprofen-(R)-α-Methylbenzylamine

Examples 8.1 to 8.6 were performed below with reference to Table 2.Racemic flurbiprofen (i) g was dissolved in a mixture of methanol (ii)ml, and toluene (iii) ml and optionally water (iv) ml. The mixture washeated to 55° C. to form a solution and (R)-α-methylbenzylamine (v) mlwas added over 10 minutes. A seed crystal of(R)-flurbiprofen-(R)-α-methylbenzylamine was added to the mixture whichwas cooled to 25° C. The precipitate was collected by filtration to givea (R)-α-methylbenzylamine salt of (R)-enriched-flurbiprofen of anenantiomeric purity of (vi)%. After recrystallisation of the precipitatefrom a mixture of methanol, toluene and water in the same ratio as usedfor the resolution stem, a solid was obtained of a further(R)-enriched-flurbiprofen-(R)-α-methylbenzylamine of an enantiomericpurity of (vii)%.

                                      TABLE 2                                     __________________________________________________________________________      (i)                         (vi)  (vii)                                       Flurbi-                                                                            (ii)   (iii) (iv) (v)  %     %                                         Ex                                                                              profen/g                                                                           Methanol/ml                                                                          Toluene/ml                                                                          H.sub.2 O/ml                                                                       MBA/ml                                                                             enrichment                                                                          enrichment                                __________________________________________________________________________    8.1                                                                             61.0 g                                                                             40.0 ml                                                                              160 ml                                                                              --   17 ml                                                                              91.2% 98.8%                                     8.2                                                                             61.0 g                                                                             70.0 ml                                                                              280 ml                                                                              --   17 ml                                                                              92.0% 99.3%                                     8.3                                                                             61.0 g                                                                             40.0 ml                                                                              160 ml                                                                              --   17 ml                                                                              91.8% 99.2%                                     8.4                                                                             61.0 g                                                                             40.0 ml                                                                              160 ml                                                                              10.0 ml                                                                            17 ml                                                                              92.4% 99.1%                                     8.5                                                                             61.0 g                                                                             40.0 ml                                                                              160 ml                                                                              2 ml 17 ml                                                                              91.8% 99.1%                                     8.6                                                                             43.1 g                                                                             20.0 ml                                                                              180 ml                                                                              --   12 ml                                                                              91.9% 99.1%                                     __________________________________________________________________________     Footnote:                                                                     1. A second recrystallisation in this example gave a further solid of         (R)enriched-flurbiprofen-(R)-α-methylbenzylamine of an enantiomeric     purity greater than 99.9%                                                

Example 9(a) Liberation of (R)-Enriched Flurbiprofen

(R)-Enriched-flurbiprofen-(R)-α-methylbenzylamine (58.7 g--prepared in asimilar manner to that described in Example 8) having an enantiomericpurity of 99.1% was heated at 80° C. for 15 minutes with a mixture ofn-heptane (160 ml), water (200 ml) and concentrated hydrochloric acid(17 ml--specific gravity 1.18). The organic layer was separated andcooled to 0° to 5° C. (R)-Enriched-flurbiprofen crystallised and wascollected, washed with n-heptane and dried in vacuo.

Example 9(b) Liberation of (S)-Enriched Flurbiprofen

In a similar manner to that described in Example 9(a),(S)-enriched-flurbiprofen is liberated from(S)-enriched-flurbiprofen-(S)-α-methylbenzylamine prepared in a similarmanner to that described in Example 7.

Example 10(a) Enantiomeric Purification of (S)-Enriched-Flurbiprofen byRecrystallisation

(S)-enriched-flurbiprofen (47.2 g) of an enantiomer purity of 98.9% wasadded to toluene (132 ml) and heated to 50° C. Crystals of(S)-flurbiprofen were added with the temperature at 42° C. and thesolution was cooled to -5° C. The solid (S)-enriched-flurbiprofen wascollected by filtration and was found to have an enantiomeric purity of99.8%.

Example 10(b) Enantiomeric Purification of (S)-Enriched-Flurbiprofen byRecrystallisation

(S)-enriched-flurbiprofen (13.5 g) of an enantiomer purity of 98.4% wasadded to toluene (26 ml) and heated to 50° C. The solution was thencooled to -10° C. The solid (S)-enriched-flurbiprofen was collected byfiltration and was found to have an enantiomeric purity of 99.8%. Yield13.0 g.

We claim:
 1. A process for the production of a product which is enrichedin a desired enantiomer of a phenylpropionic acid selected fromibuprofen or flurbiprofen which comprises the following stages:(a) aresolution, in which an α-methylbenzylamine salt of the phenylpropionicacid is prepared which is enriched in the desired enantiomer bycontacting, in a mixture of toluene and methanol as solvent, asubstantially racemic mixture of the phenylpropionic acid with anenantiomer of α-methylbenzylamine, the respective molar ratio of thesubstantially racemic phenylpropionic acid to the α-methylbenzylaminebeing in the range of about 1:0.25 to about 1:1; (b) a recrystallisationstage, in which the resulting enriched salt is recrystallised from amixture of methanol and toluene to give an α-methylbenzylamine salt ofthe phenylpropionic acid which is further enriched in the desiredenantiomer; (c) an optional liberation stage, in which thephenylpropionic acid which is further enriched in the desired enantiomeris liberated from the recrystallised salt; (d) an optionalsalt-preparation stage in which a solid salt of the phenylpropionic acidfurther enriched in the desired enantiomer is isolated, the solid saltoptionally being even further enantiomerically enriched in the desiredenantiomer; (e) a racemisation stage, in which the phenylpropionic acidenriched in the undesired enantiomer is recovered from the first motherliquor of resolution stage (a), racemised, and the racemicphenylpropionic acid is reused in a subsequent resolution stage (a); and(f) a recovery stage for the α-methylbenzylamine resolving agent, inwhich α-methylbenzylamine is recovered from the first mother liquor ofresolution stage (a) and optionally from the liberation stage (c) and isthen reused in a subsequent resolution stage (a).
 2. A process asclaimed in claim 1, in which the desired enantiomer of thephenylpropionic acid is selected from (S)-ibuprofen, (S)-flurbiprofenand (R)-flurbiprofen.
 3. A process as claimed in claim 1, in which thedesired enantiomer of the phenylpropionic acid is the (S)-enantiomerand:(a) in the resolution stage the substantially racemicphenylpropionic acid and (S)-α-methylbenzylamine are used in arespective molar ratio of about 1:0.35 to about 1:0.8, and thepreparation takes place in a mixture of methanol and toluene, in whichthe toluene comprises at least about 50% of the total mixture by volume;the temperature of the mixture is in the range from about 30° C. toabout 70° C., to form a supersaturated solution; from which aphenylpropionic acid-(S)-α-methylbenzylamine salt enriched in the(S)-enantiomer is crystallised; (b) in the recrystallisation stage thesolvent is a mixture of methanol and toluene, in which the toluenecomprises at least about 25% of the total mixture by volume; from whicha phenylpropionic acid-(S)-α-methylbenzylamine salt further enriched inthe (S)-enantiomer of the phenylpropionic acid is crystallised; (c) inthe liberation stage the (S)-α-methylbenzylamine salt offurther-(S)-enriched phenylpropionic acid, obtained from therecrystallisation stage, is acidified in a water-immiscible solvent toproduce a solution of liberated (S)-enriched-phenylpropionic acid in thewater immiscible solvent and an aqueous solution of a salt of(S)-α-methylbenzylamine from which the (S)-α-methylbenzylamine can beliberated so that it can be reused in a subsequent resolution stage (a).4. A process as claimed in claim 3, in which:(d) in the salt-preparationstage the solution of further-(S)-enriched-phenylpropionic acid in thewater-immiscible solvent obtained from the liberation stage (c) may befurther processed by one or more of the following methods:(i)crystallisation and isolation of the solid (S)-enriched-phenylpropionicacid from the solution; (ii) removal of the solvent by distillation togive a melt; (iii) where the phenylpropionic acid is ibuprofen, contactwith an aqueous solution of a sodium containing base to produce anaqueous solution of sodium ibuprofen which is separated from thewater-immiscible solvent, the aqueous solution then being diluted withacetone to crystallise further-(S)-enriched-sodium-ibuprofen; or (iv)where the phenylpropionic acid is ibuprofen, contact with (S)-lysine andwater in which the respective molar ratio of ibuprofen to (S)-lysine isin the range 1:0.5 to 1:1 to give an aqueous solution of the (S)-lysinesalt which is separated from the immiscible solvent, ethanol then beingadded to the aqueous solution to crystallisefurther-(S)-enriched-ibuprofen-(S)-lysine.
 5. A process as claimed inclaim 4, which comprises a further salt-preparation step d(v), in whichthe solid from the salt-preparation step d(i) or the melt from thesalt-preparation step d(ii) is separated and reacted in an aqueousethanolic solution with (S)-lysine in which the respective molar ratioof the phenylpropionic acid to (S)-lysine is in the range of about 1:0.5to about 1:1 to give, after crystallisation and separation, a (S)-lysinesalt of the further-(S)-enriched-phenylpropionic acid.
 6. A process asclaimed in claim 4, which comprises a further salt preparation stepd(vi), in which the sodium ibuprofen obtained from the salt-preparationstep d(iii), is acidified in the presence of a water-immiscible solventto produce a solution of further-(S)-enriched-ibuprofen in thewater-immiscible solvent which is separated, and solid(S)-enriched-ibuprofen is then crystallised and isolated.
 7. A processas claimed in claim 6, in which the water-immiscible solvent used instep d(vi) is heptane.
 8. A process as claimed in claim 4, whichcomprises a further salt-preparation step d(vii), in which the aqueoussolution of the further -(S)-enriched-sodium ibuprofen obtained fromstep d(iii), is acidified at an elevated temperature to give a meltwhich is separated from the aqueous layer and solid(S)-enriched-ibuprofen is then crystallised and isolated.
 9. A processas claimed in claim 8, in which the elevated temperature is about 60° C.10. A process as claimed in claim 1, in which the molar ratio of thesubstantially racemic phenylpropionic acid and the α-methylbenzylamineused in the resolution stage (a) is from 1:0.4 to 1:0.6.
 11. A processas claimed in claim 1 in which, the mixture of methanol and toluene usedin the resolution stage (a) comprises from about 60% to about 90%toluene by volume of the total mixture.
 12. A process as claimed inclaim 11, in which the mixture used in the resolution stage (a)comprises from about 70% to about 80% toluene by volume of the totalmixture.
 13. A process as claimed in claim 1 in which the initialtemperature of the mixture used in the resolution stage (a) is in therange from about 40° C. to about 60° C.
 14. A process as claimed inclaim 1, in which the mixture in resolution stage (a) is cooled to atemperature in the range from about -10° C. to about 30° C.
 15. Aprocess as claimed in claim 14, in which the mixture in the resolutionstage (a) is cooled to a temperature in the range from about 0° C. toabout 5° C.
 16. A process as claimed in claim 1, in which the mixtureused in the recrystallisation stage (b) comprises from about 50% toabout 80% toluene by volume of the total mixture.
 17. A process asclaimed in claim 16, in which the mixture used in the recrystallisationstage (b) comprises from about 60% to about 70% toluene by volume of thetotal mixture.
 18. A process as claimed in claim 1, in which thesolution in the recrystallisation stage (b) is cooled to a temperaturein the range from about -10° C. to about 30° C.
 19. A process as claimedin claim 18, in which the solution in the recrystallisation stage (b) iscooled to a temperature in the range from about 0° C. to about 5° C. 20.A process as claimed in claim 1, in which in the liberation stage (c),the salt of the further (S)-enriched-phenylpropionic acid obtained fromthe recrystallisation stage (b), is acidified with hydrochloric acid toproduce an aqueous solution of (S)-α-methylbenzylamine hydrochloride,which is basified, the base being extracted into toluene and the tolueneextract being reused in a subsequent resolution stage (a).
 21. A processas claimed in claim 1, in which the phenylpropionic acid is ibuprofenand the desired enantiomer is the (S)-enantiomer and:(a) the resolutionstage produces a (S)-α-methylbenzylamine salt of (S)-enriched ibuprofenof an enantiomeric purity from about 80% to about 95% by weight, and afirst mother liquor comprising (R)-enriched-ibuprofen which is used in aracemisation stage (e) to produce substantially racemic ibuprofen whichis introduced as part of the starting material used in a subsequentresolution stage (a); (b) the recrystallisation stage comprises twosteps:(i) a first recrystallisation step comprising recrystallising the(S)-enriched-ibuprofen-(S)-α-methylbenzylamine produced from theresolution stage (a), to produce(S)-enriched-ibuprofen-(S)-α-methylbenzylamine preferably of anenantiomeric purity from about 90% to 99.9% by weight, and a secondmother liquor comprising (S)-enriched-ibuprofen-(S)-α-methylbenzylamineof an enantiomeric purity from about 40% to about 70% by weight, thesecond mother liquor being introduced as part of the solvent used in asubsequent resolution step (a); (ii) a second recrystallisation stepcomprising recrystallising the(S)-enriched-ibuprofen-(S)-α-methylbenzylamine produced from the firstrecrystallisation step (b) (i), to produce substantiallyenantiomerically pure (S)-ibuprofen-(S)-α-methylbenzylamine, preferablyof an enantiomeric purity of about 99%, and a third mother liquorcomprising (S)-enriched-ibuprofen-(S)-α-methylbenzylamine of anenantiomeric purity from about 85% to about 95% by weight, the thirdmother liquor being introduced as part of the solvent used in asubsequent first recrystallisation step (b) (i).
 22. A process asclaimed in claim 21, in which the enantiomeric purity of the(S)-enriched-ibuprofen-(S)-methylbenzylamine produced from the firstrecrystallisation step (b)(i) is from about 94% to about 99% by weight.23. A process as claimed in claim 21, in which the second mother liquorcomprises (S)-enriched-ibuprofen-(S)-α-methylbenzylamine of anenantiomeric purity from about 40% to about 60% by weight.
 24. A processas claimed in claim 21, in which the third mother liquor comprises(S)-enriched-ibuprofen-(S)-α-methylbenzylamine of an enantiomeric purityfrom about 88% to about 95% by weight.
 25. A process as claimed in claim1, in which the first mother liquor from the resolution stage (a) issubjected to azeotropic distillation to remove substantially all themethanol at temperatures which avoid substantial formation ofby-products, the distillate being reused as part of the solvent in asubsequent resolution stage (a).
 26. A process as claimed in claim 25,in which the residue remaining after the distillation of the firstmother liquor is acidified to give an aqueous solution of a(S)-α-methylbenzylamine salt and an organic phase comprising(R)-enriched ibuprofen, the aqueous solution being separated andbasified to give free (S)-α-methylbenzylamine which is extracted intotoluene and reused as the resolving agent at the start of a subsequentresolution stage (a) along with (S)-α-methylbenzylamine recovered in theliberation stage (c); the organic phase comprising(R)-enriched-ibuprofen being racemised in a racemisation stage (e) toproduce substantially racemic ibuprofen which is then introduced as partof the solvent used at the start of a subsequent resolution stage (a).27. A process as claimed in claim 26, in which the residue remainingafter distillation, is acidified with hydrochloric acid to give anaqueous solution of (S)-α-methylbenzylamine hydrochloride.
 28. A processas claimed in claim 1 in which the recrystallisation stage (b) comprisesthree or more recrystallisation steps.
 29. A process as claimed in claim1 in which, at each stage of the process, liquors not comprising thephenylpropionic acid enriched in the desired enantiomer are recycled byusing them in previous stages of the process.